EDITORIAL COMMENT
Testosterone: A Novel Therapeutic Approach in Chronic Heart Failure?*
Pål Aukrust, MD, PhD , ,#,*,
Thor Ueland, PhD, ,
Lars Gullestad, MD, PhD||,¶,# and
Arne Yndestad, PhD,¶
Research Institute for Internal Medicine, Rikshospitalet, Oslo University Hospital, Oslo, Norway
Section of Clinical Immunology and Infectious Diseases, Rikshospitalet, Oslo University Hospital, Oslo, Norway
Department of Endocrinology, Rikshospitalet, Oslo University Hospital, Oslo, Norway
|| Department of Cardiology, Rikshospitalet, Oslo University Hospital, Oslo, Norway
¶ Centre for Heart Failure Research, University of Oslo, Oslo, Norway
# Faculty of Medicine, University of Oslo, Oslo, Norway
* Reprint requests and correspondence: Dr. Pål Aukrust, Section of Clinical Immunology and Infectious Diseases, Rikshospitalet, Oslo University Hospital, 0027 Oslo, Norway (Email: pal.aukrust{at}rikshospitalet.no).
Key Words: baroreflex sensitivity • congestive heart failure • exercise capacity • glucose metabolism • testosterone
Heart failure (HF) is a complex multistep disease in which a number of physiological systems participate. Intense research aims at identifying novel therapeutic options in this disorder, and most of these efforts target pathological processes in the heart (i.e., ventricular remodeling) and the renewal of the failing heart by, for example, stem cell therapy. Additionally, therapeutic modalities targeting systemic mediators such as neurohormones and cytokines have also been developed. However, despite state-of-the-art cardiovascular treatment, chronic HF is a progressive disease with high morbidity and mortality, suggesting that important pathogenic mechanisms remain unmodified by the present treatment modalities.
It is becoming more and more apparent that HF is a syndrome not only involving the heart and circulation but also encompassing other organs and organ systems such as the skeletal muscle, the lungs, and the brain. This growing "range" of comorbidities might have significant impact on both HF symptomatology and pathogenesis (1). As an example, whereas HF is associated with increased secretion of inflammatory cytokines within skeletal muscles and hypothalamus, inflammatory responses within these areas might again contribute to maladaptive responses within the myocardium (2,3). Thus, acknowledgment and proper management of these comorbidities might have an important therapeutic potential.
 |
Endocrine and metabolic disturbances in HF
|
|---|
Chronic HF is a unique metabolic syndrome characterized by perturbation of numerous endocrine, metabolic, and inflammatory parameters (4,5). These disturbances include changes in levels and sensitivity to insulin, growth hormone, and testosterone (6). Reduced insulin sensitivity and subsequent development of diabetes might represent a serious comorbidity in relation chronic HF. Indeed, more than 40% of HF patients have manifest disorders of glucose metabolism ranging from frank diabetes to impaired insulin sensitivity (6). Interestingly, decreased insulin sensitivity in HF is not explained by fat distribution and obesity. In fact, reduced glucose transporter GLUT4 in skeletal muscle has been found to predict impaired insulin sensitivity in nondiabetic chronic HF patients independently of body composition (7). Also, the combined effect of increased levels of tumor necrosis factor alpha and decreased levels of testosterone, characterizing patients with severe HF and cardiac cachexia, might adversely affect insulin sensitivity in skeletal muscle (5). These patients, characterized by a metabolic shift resulting in a state of catabolism, are associated with a particularly poor prognosis (4).
|
Skeletal muscle manifestations of HF
|
|---|
Patients with HF experience impaired exercise capacity and muscle fatigue (8). However, this fatigue does not necessarily relate to the degree of myocardial dysfunction, indicating that mechanisms unrelated to a potential peripheral hypoperfusion are of importance. Several mediators of this skeletal muscle dysfunction have been suggested, including chronic beta-adrenergic stimulation and enhanced angiotensin II activity as well as the effects of inflammatory cytokines (e.g., tumor necrosis factor alpha and interleukin 6) and reactive oxygen species (8). Also, insulin resistance, leading to an inability of insulin to promote glucose transport into skeletal muscles, has been proposed as a mediator of skeletal muscle fatigue and wasting during HF, linking these processes directly to the metabolic disturbances in HF patients (7).
|
Testosterone: a new therapeutic option in HF?
|
|---|
Chronic HF seems to be associated with decreased plasma testosterone levels (5), as mentioned in the preceding text. Thus, approximately 25% of men with chronic HF have biochemical evidence of testosterone deficiency, and low levels have been related to disease progression in HF. Moreover, myocardial cachexia, a syndrome with poor prognosis, is characterized by particularly low testosterone levels. On the basis of these issues as well as the suggested role of testosterone deficiency in insulin resistance and loss of muscle strength during HF, treatment that corrects this deficiency has become attractive. In this issue of the Journal, Caminiti et al. (9) show—in a double-blind, placebo-controlled, randomized trial in 70 elderly patients with chronic HF—that intramuscular testosterone supplementation on top of optimal therapy improves functional exercise capacity, muscle strength, insulin, and baroreflex sensitivity. Although the idea has been discussed for several years, only a few clinical trials have examined the effect of testosterone therapy in HF. The first, an uncontrolled open-label trial, found that treatment with oxymetholone improved cardiac function as determined by reduced left ventricular diameter and mass and reduced levels of brain natriuretic peptide (10). In a small double-blinded study, Pugh et al. (11) showed that HF patients receiving intramuscular testosterone injections had improved quality of life and functional capacity (walk test). In a follow-up to this pilot study, Malkin et al. (12) examined the effect of testosterone patches and found an improvement in New York Heart Association functional class and exercise capacity in HF patients. The study by Caminiti et al. (9) extends these previous findings in several ways. First, in contrast to some previous studies, they found no effects on left ventricular ejection fraction, suggesting that the effect of testosterone is not secondary to improved myocardial function. Second, although it has previously been reported that testosterone therapy might increase forearm muscle strength, the present study shows improved static and dynamic muscle performance in larger, weight-bearing muscles. Third, the improvement in muscle performance and functional capacity was accompanied by an increase in insulin sensitivity, further underscoring that testosterone deficiency, decreased insulin sensitivity, and impaired muscle performance might represent a pathogenic loop in the progression of the HF syndrome. The authors found that the improved insulin sensitivity was associated with a significant increase in body weight and body mass index, further underscoring that the mechanisms of decreased insulin sensitivity in HF are different from several other disorders, such as in obese patients with metabolic syndrome. Finally, heart failure patients have—simultaneously with neurohumoral activation—an increased peripheral chemoreflex and a decreased arterial baroreflex, and this impaired baroreceptor sensitivity has been associated with poor prognosis (13). Previous studies in animal models have shown that testosterone might improve baroreceptor sensitivity (14), and Caminiti et al. (9) show similar findings in HF patients. A disturbed interaction between CNS and the myocardium is an important feature of chronic HF, and the authors suggest that testosterone deficiency might be involved in the dysregulation of this important axis, potentially acting directly on androgen receptor within brainstem nuclei.
|
What's next?
|
|---|
The results of the testosterone studies performed thus far suggest a move forward to larger trials. However, several issues remain to be addressed before initiating such studies. First, is testosterone therapy in HF safe? High doses of testosterone might be cardiotoxic, and there are concerns that testosterone treatment might have adverse effects on coronary artery disease (5). However, with the low doses used in HF patients—many of them testosterone-deficient—these potential side effects might be negligible and, for coronary artery disease, possibly outweighed by positive effects on the "metabolic syndrome" of HF. Second, who should receive testosterone therapy? The treatment should most probably be restricted to men. But should a prerequisite be low testosterone levels? The results from the Caminiti et al. (9) study suggest that testosterone-deficient HF patients have a particularly good response to testosterone therapy. It is also conceivable that the side effect profile of testosterone will be better in this group as compared with patients with normal testosterone levels. Most of the patients that have been included in these studies so far have been elderly men, and the conclusions from these trials cannot necessarily be applied to a younger population of HF patients with testosterone levels within normal limits.
|
Conclusions
|
|---|
Testosterone treatment represents a new therapeutic approach in chronic HF that might have some potential. Studies performed thus far primarily demonstrate improved functional capacity and quality of life, with little or no effects on cardiac function, representing a more "palliative" therapeutic concept (15). However, it is not inconceivable, on the basis of the dynamic interaction between HF comorbidities and the myocardium, that these extra-cardiac effects, at least in the long-term, might translate into not only reduced morbidity but also into improved myocardial performance and reduced mortality. This aspect should be addressed in forthcoming studies.
|
Footnotes
|
|---|
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
|
References
|
|---|
1. Lang CC, Mancini DM. Non-cardiac comorbidities in chronic heart failure Heart 2007;93:665-671.[Abstract/Free Full Text]2. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6 Physiol Rev 2008;88:1379-1406.[Abstract/Free Full Text] 3. Leenen FH. Brain mechanisms contributing to sympathetic hyperactivity and heart failure Circ Res 2007;101:221-223.[Free Full Text] 4. von Haehling S, Lainscak M, Springer J, Anker SD. Cardiac cachexia: a systematic overview Pharmacol Ther 2009;121:227-252.[CrossRef][Web of Science][Medline] 5. Malkin CJ, Jones TH, Channer KS. Testosterone in chronic heart failure Front Horm Res 2009;37:183-196.[Web of Science][Medline] 6. von Haehling S, Doehner W, Anker SD. Nutrition, metabolism, and the complex pathophysiology of cachexia in chronic heart failure Cardiovasc Res 2007;73:298-309.[Abstract/Free Full Text] 7. Doehner W, Gathercole D, Cicoira M, et al. Reduced glucose transporter GLUT4 in skeletal muscle predicts insulin resistance in non-diabetic chronic heart failure patients independently of body composition Int J Cardiol 2008 Sept 6[E-pub ahead of print]. 8. Bellinger AM, Mongillo M, Marks AR. Stressed out: the skeletal muscle ryanodine receptor as a target of stress J Clin Invest 2008;118:445-453.[CrossRef][Web of Science][Medline] 9. Caminiti G, Volterrani M, Iellamo F, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure: a double-blind, placebo-controlled, randomized study J Am Coll Cardiol 2009;54:919-927.[Abstract/Free Full Text] 10. Tomoda H. Effect of oxymetholone on left ventricular dimensions in heart failure secondary to idiopathic dilated cardiomyopathy or to mitral or aortic regurgitation Am J Cardiol 1999;83:123-125.[CrossRef][Web of Science][Medline] 11. Pugh PJ, Jones RD, West JN, Jones TH, Channer KS. Testosterone treatment for men with chronic heart failure Heart 2004;90:446-447.[Free Full Text] 12. Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial Eur Heart J 2006;27:57-64.[Abstract/Free Full Text] 13. La Rovere MT, Pinna GD, Maestri R, et al. Prognostic implications of baroreflex sensitivity in heart failure patients in the beta-blocking era J Am Coll Cardiol 2009;53:193-199.[Abstract/Free Full Text] 14. El-Mas MM, Afify EA, Mohy El-Din MM, Omar AG, Sharabi FM. Testosterone facilitates the baroreceptor control of reflex bradycardia: role of cardiac sympathetic and parasympathetic components J Cardiovasc Pharmacol 2001;38:754-763.[CrossRef][Web of Science][Medline] 15. Rauchhaus M, Doehner W, Anker SD. Heart failure therapy: testosterone replacement and its implications Eur Heart J 2006;27:10-12.[Free Full Text]
Related Articles
-
Effect of Long-Acting Testosterone Treatment on Functional Exercise Capacity, Skeletal Muscle Performance, Insulin Resistance, and Baroreflex Sensitivity in Elderly Patients With Chronic Heart Failure: A Double-Blind, Placebo-Controlled, Randomized Study
- Giuseppe Caminiti, Maurizio Volterrani, Ferdinando Iellamo, Giuseppe Marazzi, Rosalba Massaro, Marco Miceli, Caterina Mammi, Massimo Piepoli, Massimo Fini, and Giuseppe M.C. Rosano
J. Am. Coll. Cardiol. 2009 54: 919-927.
[Abstract]
[Full Text]
[PDF]
-
Inside This Issue
J. Am. Coll. Cardiol. 2009 54: A29.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
J. J. Naghi, K. J. Philip, D. DiLibero, R. Willix, and E. R. Schwarz
Review: Testosterone Therapy: Treatment of Metabolic Disturbances in Heart Failure
Journal of Cardiovascular Pharmacology and Therapeutics,
March 1, 2011;
16(1):
14 - 23.
[Abstract]
[PDF]
|
|
|
|
|
|
|
D. J. Handelsman
Inadequate Masking of Testosterone
J. Am. Coll. Cardiol.,
May 18, 2010;
55(20):
2290 - 2290.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Aukrust and A. Yndestad
Reply
J. Am. Coll. Cardiol.,
May 18, 2010;
55(20):
2291 - 2291.
[Full Text]
[PDF]
|
|
|
|
Top
Endocrine and metabolic...
Skeletal muscle manifestations...